Patent GB-646701-A (GB)
Title: Improvements in or relating to basic alkyl esters and the preparation thereof
Filed: 1945-09-07
Abstract: Basic alkyl esters having the general formula <FORM:0646701/IV (b)/1> in which R is either hydrogen or an acyclic hydrocarbon or aralkyl group, R1 is naphthyl, n is an integer 2, 3 or 4, m is 1, 2, 3 or 4 and CmH2m+1 and CnH2n are of straight chained configuration are prepared in the form of their hydrogen halide salts by reacting alpha naphthyl acetic acid or an acyclic hydrocarbon or aralkyl substituted derivative thereof wherein the substituent group is attached to the alpha aliphatic carbon atom, with a dialkyl amino alkyl halide containing the group <FORM:0646701/IV (b)/2> if desired, the free basic ester may be obtained by treating the halide salt with a basic material, e.g. ammonia.  The free basic ester of the above formula may also be prepared by re-acting the acid corresponding with the acid portion of the ester with thionyl chloride and reacting the acid chloride so formed in an inert organic solvent with an excess of the dialkylamino alcohol corresponding with the alcoholic portion of the ester, generally by refluxing, filtering off dialkyl amino alcohol hydrochloride and distilling the resulting solution of free ester to remove the solvent.  In the first method, substantially equimolecular proportions of acid and amino alkyl halide are heated preferably in presence of a low boiling organic solvent, e.g. isopropyl alcohol, butyl alcohol or benzene, the solvent being removed thereafter and the residue fractionally crystallized from a suitable organic solvent or solvent mixture.  Salts of the basic ester may be prepared by double decomposition of the hydrohalide salt with the appropriate anhydrous acid or by reacting the free basic ester with the desired acid or its anhydride, preferably in a non-polar solvent such as diethyl ether.  The compounds are stated to have value as antispasmodics.  In examples, a -(a -naphthyl)butyric acid and b -diethylamino ethyl chloride are refluxed in anhydrous isopropanol, the solvent distilled off under reduced pressure and the residue, b - diethylamino - ethyl a  - (a  - naphthyl) normal butyrate hydrochloride, crystallized from anhydrous ethyl acetate; the free base is obtained by treating the hydrochloride with sodium carbonate in aqueous solution and extracting with anhydrous diethyl ether.  In like manner, there are prepared b -diethylaminoethyl a -naphthyl-acetate hydrochloride, g -diethylamino - propyl a  - naphthyl acetate hydrochloride, b  - diethylamino - ethyl a -(a  - naphthyl) - propionate hydrochloride, g -diethylamino - propyl a  - (a  - naphthyl) - propionate hydrochloride, g  - diethylamino-propyl a  - (a  - naphthyl) - normal - butyrate hydrochloride; in similar fashion, such compounds as b -diethylamino-ethyl a -(a -naphthyl) normal pentanoate and its hydrochloride, and g  - diethylamino - propyl a  - (a  - naphthyl)-normal hexanoate and its hydrochloride and bromide may be formed from appropriate acid and amino alkyl halide.  It is stated that by either of the main methods there may also be prepared b  - dipropylamino - ethyl a  - (a -naphthyl) - b  - phenyl - propionate hydrochloride, di - n - butylamino - propyl a  - (a -naphthyl) - n - hexanoate hydrobromide, b -dipropylamino - ethyl a  - (a  - naphthyl) - b -phenyl butyrate hydrochloride and d  - di - n-butylamino - n - butyl a  - (a  - naphthyl) - n-hexenoate - D  - 4 - hydrochloride.  Reference is made to the preparation of these salts: b -diethylamino - ethyl a  - naphthyl - acetate metho - sulphate, g  - diethylamino - propyl a  - (a  - naphthyl) propionate hydroiodide, b  - dipropylamino - ethyl a  - (a  - naphthyl) - n-butyrate hydroacetate and g -diethylaminopropyl a  - (a  - naphthyl) - n - butyrate tartrate.  The Specification as open to inspection under Sect. 91 relates to the preparation of esters of the above general formula, and their salts, wherein R1 is naphthyl or xenyl and R is hydrogen or a hydrocarbon radical including cycloalkyl and aryl radicals, by p  the above-described methods.  Reference is made to the preparation of b -diethylamino-ethyl-p-xenyl acetate hydrochloride, g -diethylamino-propyl-p-xenyl acetate hydrochloride, b -dibutylamino, ethyl a -(p-xenyl)-phenyl acetate hydrochloride g -diethylamino-propyl a -(p-xenyl)-phenyl acetate hydrochloride, g -diethylamino-propyl a -(p-xenyl-cyclohexyl acetate hydrochloride, b -diethylamino - ethyl a  - (p - xenyl) - propionate hydrochloride, g - diethylamino - propyl a -(p-xenyl)-propionate hydrochloride, g -diethylamino - propyl a  - (p - xenyl) - n - butyrate hydrochloride, g  - diethylamino - propyl a -(p - xenyl) - n - pentanoate hydrochloride, b -diethylamino - ethyl a  - (p - xenyl) - n - hexanoate and its hydrochloride, b -dibutylaminoethyl a  - (p - xenyl) - n - hexanoate and its hydrochloride, dimethylaminoethyl ester of a -methyl - p - xenyl acetic acid, g  - dipropylamino - propyl a  - (p - xenyl) - propionate and its hydrochloride, d -diethylamino-n-butyl a -(p-xenyl)-cyclohexyl acetate and its hydrochloride, b -dipropyl amino ethyl a -(p-xenyl)-phenyl acetate and its hydrochloride and to the following additional naphthyl acetates: g -diethylamino - propyl a  - (a  - naphthyl)-phenyl acetate and its hydrochloride, b -diethylamino - ethyl a  - (a  - naphthyl) - phenyl acetate hydrochloride, b -di-n-butylamino ethyl a - (a  - naphthyl) - phenyl acetate hydrochloride, g  - di - n - propyl amino - n - butyl a  - (a  - naphthyl) - n - butyrate hydrochloride, g  - di - n - butyl amino - propyl a  - (a  - naphthyl) phenyl acetate hydrochloride, b -diethylamino ethyl a  - (a - naphthyl) cyclohexyl acetate and its hydrochloride.  a -(a -naphthyl)-butyric, pentanoic and hexanoic acids are prepared by reacting diethyl a -naphthyl malonate with sodium in benzene and then with ethyl, propyl or butyl iodide, destroying excess of sodium with alcohol, adding water and diethyl ether, removing a resulting ether-benzene solution of diethyl alkyl a -naphthyl malonate, isolating the ester, treating with alcoholic potash, distilling off alcohol, neutralizing the residue with hydrochloric acid, removing the precipitated 2-(a -naphthyl) 2-alkyl malonic acid and heating at 180 DEG  C. to decarboxylate to the desired acid.  This subject-matter does not appear in the Specification as accepted.